The coexistence of PrP amyloidosis with neurofibrillary tangles is the central pathologic feature of Gerstmann-Straussler-Scheinker disease (GSS), in the Indiana Kindred (IK). This large kindred has been the object of extensive neurological, neuropathologic, biochemical, genetic, and molecular investigations. GSS in the IK (GSS-IK), is a dominant disorder characterized by ataxia, Parkinsonism and dementia, and is caused by a mutation at codon 198 of the PRNP gene. During the past three years, we have expanded our studies of PrP amyloidosis with neurofibrillary tangles and found that the co-existence of these two lesions is present in other genetic forms of GSS. We propose to study the prodromal stage, the evolution, and the natural history of GSS-IK in individuals at-risk, by examining them neuropsychologically, by eye movement studies, and by positron emission tomography. Extensive neuropathologic analysis on ten autopsy cases will be carried out by analyzing the amyloid and pre-amyloid deposits and their distribution in the central nervous system. We will correlate this neuropathologic data with biochemical studies directed to further characterize the amyloidogenic peptides and the pathologic chaperone proteins involved in prion protein (PrP) amyloidosis. We will search for regional differences in PrP isoforms that may correlate with pathologic topography. Furthermore, neurofibrillary tangles will be studied and compared with those of Alzheimer disease in an attempt to define the abnormal phosphorylation sites in NFT of GSS. Finally, to further our understanding of the possible mechanisms whereby PRNP mutations lead to disease, we will study PrP expression and processing at the cellular level.